Daclatasvir, a symmetric drug for an anti-symmetric target

Immunotherapy has become a cornerstone in cancer treatment, with anti-PD-L1 antibodies effectively used across various cancers. Although these therapies have shown success, antibodies face limitations in bioavailability compared to low molecular mass compounds. An alternative strategy is to stabilize PD-L1 homodimers to prevent their immunosuppressive activity. The homodimer interface forms a tunnel-like cavity that can accommodate small molecules. However, no small drugs targeting PD-L1 homodimers have been approved for cancer treatment. Drug repurposing offers a promising approach to bridge this gap. In this study, we sought to identify potential PD-L1 inhibitors among FDA-approved drugs using virtual screening, followed by molecular docking, molecular dynamics simulations, and MM/PBSA binding energy calculations. Our results indicate that daclatasvir, an FDA-approved antiviral for hepatitis C, forms a stable and energetically favorable complex with the PD-L1 homodimer, suggesting it as a promising candidate for further investigation in cancer immunotherapy. Due to its symmetry, daclatasvir simultaneously interacts with both PD-L1 monomers in an equivalent manner, bridging the dimer interface. Its biphenyl core anchors at the center of the tunnel, the imidazole rings position at the entrances, and the pyrrolidine rings remain exposed to the solvent. Our in-depth characterization of the binding mode of daclatasvir clarifies its binding mechanism, and recent experimental findings have also indicated that daclatasvir binds to PD-L1, supporting its potential in this new context.